Hsp90 is an abundant protein which has a role in cell viability and which exhibits dual chaperone functions (J. Cell Biol. (2001) 154:267-273, Trends Biochem. Sci. (1999) 24:136-141). It plays a role in the cellular stress-response by interacting with many proteins after their native conformations have been altered by various environmental stresses, such as heat shock, ensuring adequate protein-folding and preventing non-specific aggregation (Pharmacological Rev. (1998) 50:493-513). Recent results suggest that Hsp90 may also play a role in buffering against the effects of mutation, presumably by correcting inappropriate folding of mutant proteins (Nature (1998) 396:336-342). Hsp90 also has regulatory roles under normal physiological conditions and is responsible for the conformational stability and maturation of a number of specific client proteins (see. Expert. Opin. Biol Ther. (2002) 2(1): 3-24).
Hsp90 antagonists are currently being explored in a large number of biological contexts where a therapeutic effect can be obtained for a condition or disorder by inhibiting one or more aspects of Hsp90 activity.
Geldanamycin is a macrocyclic lactam that is a member of the benzoquinone-containing ansamycin family of natural products. Geldanamycin's nanomolar potency and apparent selectivity for killing tumor cells, as well as the discovery that its primary target in mammalian cells is Hsp90, has stimulated interest in its development as an anti-cancer drug. However, its extremely low solubility and the association of hepatotoxicity with the administration of geldanamycin have led to difficulties in developing an approvable agent for therapeutic applications. In particular, geldanamycin has poor water solubility, making it difficult to deliver in therapeutically effective doses.
More recently, attention has focused on 17-amino derivatives of geldanamycin (“geldanamycin analogs”), in particular 17-AAG, showing reduced hepatotoxicity while maintaining Hsp90 binding. See U.S. Pat. Nos. 4,261,989; 5,387,584; and 5,932,566. Like geldanamycin, these 17-amino derivatives have very limited aqueous solubility. Consequently, there is an unmet need to develop additional pharmaceutical compositions of geldanamycin analogs, such as 17-AG and 17-AAG, and solid forms thereof.